ProjectSummary Cellularsenescenceisatumorsuppressivecellgrowtharresttriggeredbyinducerssuchas activationofoncogenesandchemotherapeutics.However,senescentcellsareviableandmaypromote tumorprogressionandtherapyrelapsethroughsecretionoffactorssuchascytokines,chemokinesand growthfactors,termedthesenescence-associatedsecretoryphenotype(SASP).Thus,itwouldbeideal toenhancesenescence-associatedgrowtharrestwhilelimitingSASPbecausethismayleadtoadurable therapeuticoutcome.Notably,itremainstobedeterminedwhethersilencingofproliferationgenesand upregulationofSASPgenesarecoupledatthemolecularlevel.Thus,theoverallgoalofthisproposalis toinvestigatethemechanismthatcoordinatesthesilencingofproliferationgenesandtheupregulationof SASPgenesduringsenescenceanditsimplicationsincancerandresponsetotherapy.HMGB2isa chromatinarchitectureproteinthatbindstoDNAwithoutsequencespecificity.Ourpreliminarydata suggestthatHMGB2orchestratesgeneexpressionreprogrammingduringsenescencebyactingasa molecularswitch.Specifically,lossofHMGB2fromgenomiclociofproliferationgenescontributestotheir silencing.Incontrast,HMGB2?sredistributiontoSASPgeneslocipromotestheirexpression.Consistent withitsroleinsenescence,HMGB2isoftenupregulatedinepithelialovariancancer(EOC)andits expressioncorrelateswithEOCprogression.Further,expressionofHMGB2positivelycorrelateswithits targetproliferationgenesinEOCs.Basedonthesefindings,ourcentralhypothesisisthatHMGB2 orchestratesgeneexpressionreprogrammingtoregulatetheswitchfromproliferationtosenescence. WealsohypothesizethatHMGB2contributestoEOCbysuppressingsenescenceandpromotes platinum-basedtherapyrelapsebydrivingSASP.Accordingly,twospecificaimsareproposed:Aim1: ToelucidatethemolecularmechanismbywhichHMGB2regulatessenescence;?andAim2:To determinetheroleofHMGB2inEOCandtherapyrelapse.Theproposedstudiesarehighlynovel becausethisisthefirststudytoexploreanovelmolecularmechanismthatorchestratesthesilencingof proliferation-promotinggenesandtheupregulationofSASPgenesduringsenescence.Thus,ourstudies areparadigmshiftingintheirpotentialtoelucidatethemolecularbasisofgeneexpression reprogrammingduringsenescence.Theresearchproposedisofhighimpactbecausetheywilllaythe criticalfoundationforultimatelydevelopingnovelstrategiesthatharnessthetumor-suppressivebenefitof senescence,whilelimitingthedetrimentalaspectsofSASPtoultimatelyachievedurabletherapy outcome.Therefore,thecurrentstudywillnotonlyprovidecriticalmechanisticinsightsintogene expressionreprogrammingduringsenescence,butwillalsohavefar-reachingimplicationsforthe developmentofsenescence-basedtherapeuticstrategies.